Postoperative pain is a major morbidity of surgery. The development of novel analgesics is hindered, however, by a fundamental gap in understanding how pain is regulated in the brain. The long-term goal of this proposal is to understand the central regulation of postoperative pain. The overall objective of this application is to define the role of glutamate signaling in the projection from the prefrontal cortex (PFC) to the nucleus accumbens (NAc) for the regulation of acute and chronic postoperative pain. The central hypothesis is that glutamate inputs from excitatory neurons in the PFC to the D1-type neurons in the NAc decreases pain and that AMPAkines can enhance glutamate signaling in this projection to treat postoperative pain. This hypothesis is supported by preliminary data showing that optogenetic activation of the PFC-NAc circuit inhibits persistent pain, and that systemic and intra-NAc or intra-PFC delivery of AMPAkines relieves chronic postoperative pain. It is further supported by our recent findings that PFC excitatory neurons are activated by pain. In Aim 1, the analgesic effect of the glutamate projection from the PFC to the NAc will be defined in two rodent models: the paw incision model for acute postoperative pain and the spared nerve injury model for persistent postoperative pain. We will image excitatory and inhibitory neurons in the PFC in these pain models. We will also examine the impact of AMPAkine analgesic treatment on distinct types of PFC neurons. In Aim 2, we will optogenetically activate the PFC and image D1- vs D2-type neurons in the NAc to examine which class of neurons are activated by this glutamatergic analgesic projection. We will also study the impact of AMPAkine treatment on these NAc neurons. This project is innovative because it applies a new systems neuroscience approach to uncover a novel central pain- inhibitory mechanism. The work is significant because it identifies the PFC-NAc pain-inhibitory circuit as a potential target for neuromodulation therapies and, more importantly, it establishes AMPAkines as postoperative drugs that can treat both sensory and affective symptoms of pain while opposing opioid-induced hypoventilation, laying the groundwork for clinical trials.